Skip to main content
Log in

Proinvasive extracellular matrix remodeling for tumor progression

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Cancer is a systemic disease in which neoplastic cells interact with multiple types of non-neoplastic stromal cells as well as non-cellular components. The extracellular matrix (ECM) is a non-cellular component that is aberrantly regulated in many types of tumor microenvironments. Since the ECM generally maintains the tissue structure and provides mechanical forces in the tumor microenvironment, it has been simply assumed to act as a physical barrier for cancer metastasis and have a passive role in cancer progression. However, a substantial body of evidence has suggested that ECM remodeling influences many aspects of cancer cell behaviors and its importance has attracted attention in cancer biology. Abnormal ECM affects cancer progression through several ways such as inducing hypoxia, immune cells interaction by promoting mesenchymal shift and cell transformation. Accordingly, in this review we summarize and discusses the role of the ECM in modulating epithelial cells and surrounding stomatal cell components and considers its prospects in cancer biology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Alonso-Nocelo M, Raimondo TM, Vining KH, Lopez-Lopez R, De La Fuente M, Mooney DJ (2018) Matrix stiffness and tumor-associated macrophages modulate epithelial to mesenchymal transition of human adenocarcinoma cells. Biofabrication 10:035004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bourguignon LY, Zhu H, Shao L, Chen YW (2001) CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem 276:7327–7336

    Article  CAS  PubMed  Google Scholar 

  • Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP (2010) HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: autophagy drives compartment-specific oncogenesis. Cell Cycle 9:3534–3551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266

    Article  CAS  PubMed  Google Scholar 

  • Cox TR, Bird D, Baker AM, Barker HE, Ho MWY, Lang G, Erler JT (2013) LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Can Res 73:1721–1732

    Article  CAS  Google Scholar 

  • Cox TR, Rumney RMH, Schoof EM, Perryman L, Hoye AM, Agrawal A, Bird D, Ab Latif N, Forrest H, Evans HR, Huggins ID, Lang G, Linding R, Gartland A, Erler JT (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR (1993) Activity of type-IV collagenases in benign and malignant breast disease. Br J Cancer 67:1126–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9:1392–1400

    Article  CAS  PubMed  Google Scholar 

  • Gilkes DM, Semenza GL, Wirtz D (2014) Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer 14:430–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gutschalk CM, Yanamandra AK, Linde N, Meides A, Depner S, Mueller MM (2013) GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression. Cancer Med 2:117–129

    Article  CAS  PubMed  Google Scholar 

  • Hall PA, Watt FM (1989) Stem cells: the generation and maintenance of cellular diversity. Development 106:619–633

    CAS  PubMed  Google Scholar 

  • Hegedus B, Marga F, Jakab K, Sharpe-Timms KL, Forgacs G (2006) The interplay of cell-cell and cell-matrix interactions in the invasive properties of brain tumors. Biophys J 91:2708–2716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326:1216–1219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang D, Lim SY (2016) Influence of immune myeloid cells on the extracellular matrix during cancer metastasis. Cancer Microenviron 9:45–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  CAS  PubMed  Google Scholar 

  • Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, Macdonald DD, Jin DK, Shido K, Kerns SA, Zhu ZP, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim EJ, Suh Y, Kim S, Kang SG, Lee SJ (2018) Force-mediated proinvasive matrix remodeling driven by tumor-associated mesenchymal stem-like cells in glioblastoma. BMB Rep 51:182–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3:a005058

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madsen CD, Pedersen JT, Venning FA, Singh LB, Moeendarbary E, Charras G, Cox TR, Sahai E, Erler JT (2015) Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis. EMBO Rep 16:1394–1408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maeda T, Sakabe T, Sunaga A, Sakai K, Rivera AL, Keene DR, Sasaki T, Stavnezer E, Iannotti J, Schweitzer R, Ilic D, Baskaran H, Sakai T (2011) Conversion of mechanical force into TGF-beta-mediated biochemical signals. Curr Biol 21:933–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Merdad A, Karim S, Schulten HJ, Dallol A, Buhmeida A, Al-Thubaity F, Gari MA, Chaudhary AG, Abuzenadah AM, Al-Qahtani MH (2014) Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis. Anticancer Res 34:1355–1366

    CAS  PubMed  Google Scholar 

  • Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, Mcghee E, Timpson P, Leach J, Mcgarry L, Shanks E, Bailey P, Chang D, Oien K, Karim S, Au A, Steele C, Carter CR, Mckay C, Anderson K, Evans TRJ, Marais R, Springer C, Biankin A, Erler JT, Sansom OJ (2015) Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. Embo Mol Med 7:1063–1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagaharu K, Zhang XH, Yoshida T, Katoh D, Hanamura N, Kozuka Y, Ogawa T, Shiraishi T, Imanaka-Yoshida K (2011) Tenascin C induces epithelial-mesenchymal transition-like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. Am J Pathol 178:754–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naylor MS, Stamp GW, Davies BD, Balkwill FR (1994) Expression and activity of Mmps and their regulators in ovarian-cancer. Int J Cancer 58:50–56

    Article  CAS  PubMed  Google Scholar 

  • Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  CAS  PubMed  Google Scholar 

  • Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng XF, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, Lebleu VS, Kalluri R (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  CAS  PubMed  Google Scholar 

  • Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersa IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rozario T, Desimone DW (2010) The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol 341:126–140

    Article  CAS  PubMed  Google Scholar 

  • Rupp T, Langlois B, Koczorowska MM, Radwanska A, Sun Z, Hussenet T, Lefebvre O, Murdamoothoo D, Arnold C, Klein A, Biniossek ML, Hyenne V, Naudin E, Velazquez-Quesada I, Schilling O, Van Obberghen-Schilling E, Orend G (2016) Tenascin-C orchestrates glioblastoma angiogenesis by modulation of pro- and anti-angiogenic signaling. Cell Rep 17:2607–2619

    Article  CAS  PubMed  Google Scholar 

  • Sanz-Moreno V, Gaggioli C, Yeo M, Albrengues J, Wallberg F, Viros A, Hooper S, Mitter R, Feral CC, Cook M, Larkin J, Marais R, Meneguzzi G, Sahai E, Marshall CJ (2011) ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20:229–245

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Yoshida T, Okabe M, Zhou KX, Wang F, Soko C, Saito S, Nikaido T (2017) Isolation of stem-like cancer cells in primary endometrial cancer using cell surface markers CD133 and CXCR4. Transl Oncol 10:976–987

    Article  PubMed  PubMed Central  Google Scholar 

  • Ulrich TA, De Pardo EMJ, Kumar S (2009) The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res 69:4167–4174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Umesh V, Rape AD, Ulrich TA, Kumar S (2014) Microenvironmental stiffness enhances glioma cell proliferation by stimulating epidermal growth factor receptor signaling. PLoS ONE 9:e101771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watt FM, Huck WT (2013) Role of the extracellular matrix in regulating stem cell fate. Nat Rev Mol Cell Biol 14:467–473

    Article  CAS  PubMed  Google Scholar 

  • Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296:1046–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wyckoff J, Wang WG, Lin EY, Wang YR, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Can Res 64:7022–7029

    Article  CAS  Google Scholar 

  • Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30:245–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia S, Lal B, Tung B, Wang S, Goodwin CR, Laterra J (2016) Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation. Neuro Oncol 18:507–517

    Article  CAS  PubMed  Google Scholar 

  • Yoo KC, Suh Y, An Y, Lee HJ, Jeong YJ, Uddin N, Cui YH, Roh TH, Shim JK, Chang JH, Park JB, Kim MJ, Kim IG, Kang SG, Lee SJ (2018) Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation. Oncogene 37:3317–3328

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean government, through its National Nuclear Technology Program (2016R1E1A1A01942075).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Su-Jae Lee.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaushik, N., Kim, S., Suh, Y. et al. Proinvasive extracellular matrix remodeling for tumor progression. Arch. Pharm. Res. 42, 40–47 (2019). https://doi.org/10.1007/s12272-018-1097-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-018-1097-0

Keywords

Navigation